Research Paper Volume 11, Issue 12 pp 3969—3992

AGTR1 promotes lymph node metastasis in breast cancer by upregulating CXCR4/SDF-1α and inducing cell migration and invasion

Yuxi Ma 1, , Zihan Xia 1, , Chunmei Ye 2, , Chong Lu 3, , Sheng Zhou 4, , Juan Pan 5, , Cuiwei Liu 1, , Jieying Zhang 1, , Tao Liu 1, , Ting Hu 1, , Linka Xie 1, , Gang Wu 1, , Yanxia Zhao 1, ,

  • 1 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
  • 2 Department of Breast Surgery, Wuhan Women and Children’s Health Care Center, Wuhan 430022, China
  • 3 Department of Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
  • 4 Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
  • 5 Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

received: December 30, 2018 ; accepted: June 13, 2019 ; published: June 19, 2019 ;

https://doi.org/10.18632/aging.102032
How to Cite

Copyright: Ma et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The angiotensin II type I receptor (AGTR1) has a strong influence on tumor growth, angiogenesis, inflammation and immunity. However, the role of AGTR1 on lymph node metastasis (LNM) in breast cancer, which correlates with tumor progression and patient survival, has not been examined. AGTR1 was highly expressed in lymph node-positive tumor tissues, which was confirmed by the Oncomine database. Next, inhibition of AGTR1 reduced tumor growth and LNM in orthotopic xenografts by bioluminescence imaging (BLI). Losartan, an AGTR1-specific inhibitor, decreased the chemokine pair CXCR4/SDF-1α levels in vivo and inhibited AGTR1-induced cell migration and invasion in vitro. Finally, the molecular mechanism of AGTR1-induced cell migration and LNM was assessed by knocking down AGTR1 in normal cells or CXCR4 in AGTR1high cells. AGTR1-silenced cells treated with losartan showed lower CXCR4 expression. AGTR1 overexpression caused the upregulation of FAK/RhoA signaling molecules, while knocking down CXCR4 in AGTR1high cells downregulated these molecules. Collectively, AGTR1 promotes LNM by increasing the chemokine pair CXCR4/SDF-1α and tumor cell migration and invasion. The potential mechanism of AGTR1-mediated cell movement relies on activating the FAK/RhoA pathway. Our study indicated that inhibiting AGTR1 may be a potential therapeutic target for LNM in early-stage breast cancer.

Abbreviations

AGTR1: the angiotensin II type I receptor; BLI: bioluminescence imaging; FAK: focal adhesion kinase; RhoA: Ras homolog gene family member A; ALND: axillary lymph node dissection; Ang II: angiotensin II; RAS: renin angiotensin system; EMT: epithelial-mesenchymal transition; LOS: losartan; LNM: lymph node metastasis; ARBs: angiotensin-receptor blockers.